Effect of delayed cerebral vasospasm on cerebrovascular endothelin A receptor expression and function

Abstract

Object The key role in the development of cerebral vasospasm after subarachnoid hemorrhage (SAH) is increasingly assigned to endothelin (ET)-1. Constriction of the cerebrovasculature by ET-1 is mainly mediated by the ETA receptor but is putatively altered during the development of cerebral vasospasm. Therefore, the aim in the present study was to characterize these alterations, with the emphasis on the ETA receptor. Methods Cerebral vasospasm was induced using the rat double-hemorrhage model and proven by perfusion weighted magnetic resonance imaging. Rats were killed on Day 5 after SAH, and immunohistochemical staining for ETA receptors was performed. The isometric force of basilar artery ring segments with (E+, control group) and without (E−, SAH group) endothelial function was measured. Concentration effect curves (CECs) for ET-1 were constructed by cumulative application in the absence and presence of the selective ETA receptor antagonist clazosentan (10−8 or 10−7 M). Results The CEC for E+ segments was significantly shifted to the left after SAH by a factor of 3.7, whereas maximum contraction was unchanged. In E− segments, the CECs were not shifted during cerebral vasospasm but the maximum contraction was significantly enhanced. The inhibitory potency of clazosentan yielded a pA2 value of 8.6 ± 0.2. Immunohistochemical staining of the smooth-muscle layer showed no significant increase of ETA receptor expression, but positive staining occurred in the endothelial space after SAH. Conclusions The present data indicate an enhanced contractile effect of the smooth-muscle ETA receptors in cases of cerebral vasospasm. The inhibitory potency of clazosentan on this contraction is increased. Furthermore, some evidence for an ETA receptor and an endothelium-dependent vasoactive effect after SAH is provided.